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COX6A2 variants cause a muscleāspecific cytochrome c oxidase deficiency
- Source :
- Annals of Neurology. 86:193-202
- Publication Year :
- 2019
- Publisher :
- Wiley, 2019.
-
Abstract
- OBJECTIVE Cytochrome c oxidase (COX) deficiency is a major mitochondrial respiratory chain defect that has vast genetic and phenotypic heterogeneity. This study aims to identify novel causative genes of COX deficiency with only striated muscle-specific symptoms. METHODS Whole exome sequencing was performed in 2 unrelated individuals who were diagnosed with congenital myopathy and presented COX deficiency in muscle pathology. We assessed the COX6A2 variants using measurements of enzymatic activities and assembly of mitochondrial respiratory chain complexes in the samples from the patients and knockout mice. RESULTS Both patients presented muscle weakness and hypotonia in 4 limbs along with facial muscle weakness. One patient had cardiomyopathy. Neither patient exhibited involvement from other organs. Whole exome sequencing identified biallelic missense variants in COX6A2, which is expressed only in the skeletal muscle and heart. The variants detected were homozygous c.117C > A (p.Ser39Arg) and compound heterozygous c.117C > A (p.Ser39Arg) and c.127T > C (p.Cys43Arg). We found specific reductions in complex IV activities in the skeletal muscle of both individuals. Assembly of complex IV and its supercomplex formation were impaired in the muscle. INTERPRETATION This study indicates that biallelic variants in COX6A2 cause a striated muscle-specific form of COX deficiency. ANN NEUROL 2019;86:193-202.
- Subjects :
- Male
0301 basic medicine
medicine.medical_specialty
Adolescent
Cytochrome-c Oxidase Deficiency
Muscle Proteins
Biology
Compound heterozygosity
Electron Transport Complex IV
Mice
03 medical and health sciences
Fatal Outcome
0302 clinical medicine
Internal medicine
medicine
Animals
Humans
Amino Acid Sequence
Muscle, Skeletal
Exome sequencing
Mice, Knockout
Facial Muscle Weakness
Genetic Variation
Infant
Skeletal muscle
Muscle weakness
medicine.disease
Congenital myopathy
Hypotonia
Pedigree
Mice, Inbred C57BL
HEK293 Cells
030104 developmental biology
Endocrinology
medicine.anatomical_structure
Mitochondrial respiratory chain
Neurology
Neurology (clinical)
medicine.symptom
030217 neurology & neurosurgery
HeLa Cells
Subjects
Details
- ISSN :
- 15318249 and 03645134
- Volume :
- 86
- Database :
- OpenAIRE
- Journal :
- Annals of Neurology
- Accession number :
- edsair.doi.dedup.....a73f05cddbef1ee2471e55140ff531e2